The cumulative incidence of lysosomal storage diseases has been estimated at 1 in 10,000 live births with 65% demonstrating significant CNS involvement. Systemic therapies can effectively alleviate visceral disease, but the relative impermeability of the human blood-brain barrier has prevented effective correction of CNS deficits. Thus, directed application of enzyme to the brain is required. We hypothesize that recombinant feline immunodeficiency virus (FIV) vectors can be developed and used to complement the enzyme deficiency and accompanying CNS disease. Because many lysosomal enzymes are secreted as well as traffic directly to the lysosome, and uptake of secreted enzyme occurs from transduced and non-transduced cells, delivery to all deficient cells is not required. However, enzyme must reach a significant proportion of the brain for benefit, but optimal methods to accomplish global correction for the LSDs are unknown. Novel envelopes for pseudotyping FIV, identified during the prior award, give us the opportunity to now test how best to achieve this. We will use the beta-glucuronidase deficient (MPS VII) mouse as a model of progressive CNS lysosomal storage disease to address our questions. Two hypotheses will be tested 1) delivery of FIV pseudotyped with envelopes that provide broad transduction profiles or delivery of enzyme from the CSF will reverse functional deficits in the MPS VII mouse brain and 2) an envelope that provides for transduction of resident neuroprogenitor cells will correct functional deficits in the MPS VII brain. Our data will reveal the levels of enzyme required for correction of functional deficits, and the optimal cell targets for achieving persistent global correction of neuropathology and functional restoration in MPS VII brain. The importance of these studies extends to other lysosomal storage diseases affecting the CNS, and many neuropathological conditions for which lentivirus-mediated therapy may be beneficial in future years.